Expeditious synthesis of 2,3-dihydro-2-alkoxy-3-methylenebenzofurans from N-benzofuran-3-ylmethyl N,N,N-trialkylammonium bromides: a new approach to access the natural product, 2-hydroxy-3-methylene-6-methyl-2, 3-dihydrobenzofuran

Article abstract of DOI:10.1016/j.tet.2009.06.049

A highly efficient strategy was developed to construct a natural product-based library of 2-alkoxy-3-methylene-2,3-dihydrobenzofurans from N-benzofuran-3-ylmethyl N,N,N-trialkylammonium bromides.

Full text of DOI:10.1016/j.tet.2009.06.049

Tetrahedron 65 (2009) 6986–6990
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Expeditious synthesis of 2,3-dihydro-2-alkoxy-3-methylenebenzofurans from
N-benzofuran-3-ylmethyl N,N,N-trialkylammonium bromides:
a new approach to access the natural product, 2-hydroxy-
3-methylene-6-methyl-2, 3-dihydrobenzofuran
*
Yuanxiang Wang, Ao Zhang
Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 April 2009
Received in revised form 5 June 2009
Accepted 12 June 2009
A highly efficient strategy was developed to construct a natural product-based library of 2-alkoxy-3-
methylene-2,3-dihydrobenzofurans from N-benzofuran-3-ylmethyl N,N,N-trialkylammonium bromides.
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 18 June 2009
Keywords:
Benzofuran
3-Methylene-2,3-dihydrobenzofuran
Natural product
Expeditious synthesis
1. Introduction
2-(prop-1-en-2-yl)phenyl acetate (7), followed by SeO2-oxi-
dization and saponification. The last synthesis was reported in
Benzofurans belong to one of the most studied structural units
in both the synthetic and medicinal chemistry community.1 They
are widely embedded in many biologically interesting natural
products and synthetic analogues.1,2 Among this large family,
benzofuranols represent a fairly small family featured with the
furan-2,3 double bond shifting from inside to outside of the furan
fragment and with a C2-hemiacetal function.3 This series of com-
pounds were barely studied due to the limited source and very few
available synthetic protocols. The prototypic member of this
unique class is compound 1, a naturally occurring benzofuranol.
This compound was first isolated from the roots of the Heleium
hybrid in 1969 and reported to have a strong nematicidal activity in
vitro.3a This compound has become a challenging synthetic target
and till now only three syntheses have been reported (Fig. 1). The
first synthesis was reported by Bohlmann and co-workers3a who in
1969 used 6-methylbenzofuran-3(2H)-one (5) as the key in-
termediate followed by a C2-alkylation, MeMgI-nucleophilic at-
tack at the carbonyl moiety in 4 and H2O-elimination of 3. In 1977,
Divakar et al.4 reported another synthesis starting from 4,7-di-
methyl-2H-chromen-2-one (8) which was first pyrrolyzed to yield
1997 by Snieckus and co-workers5 who first developed an anionic
homologous Fries rearrangement strategy to construct the key
intermediate 11 and then converted it to 3-(methoxymethylene)-
6-methylbenzofuran-2(3H)-one (10) followed by sequential re-
duction and base-induced retro-Michael reaction. The former two
synthetic methods suffered from very low yields and harsh re-
action conditions, and the third synthesis, although claiming to
provide an improvement over the previous methods, provided the
target compound (1) in only 42–56% yield from intermediate 11.
Therefore, a more practical method allowing for an expeditious
access to benzofuranol (1) is still needed.
We recently initiated an approach to synthesize a large library of
3-alkoxymethyl benzofurans (I, Fig. 2) by reacting bromide 126 with
a line of sodium alkoxides for our high-throughput screening (HTS)
program. Although the exact mechanism of this substitution re-
action was not investigated, we envisioned that it may proceed by
formation of an active species A, which is then converted to product
I through a SN1 or SN2 nucleophilic substitution pathway (Fig. 2).7
Alternatively, a conjugated species B might also be formed during
this transformation, and could likely provide compound II with the
furan-2,3 double bond shifting to the outside of the ring system.
Since the formation of aromatic product I through species A is
preferred in most cases, the production of compound II through
species B would be largely dependent on the leaving ability of the X
* Corresponding author. Tel./fax: þ86 21 50806035.
E-mail address: aozhang@mail.shcnc.ac.cn (A. Zhang).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.049

Y. Wang, Ao. Zhang / Tetrahedron 65 (2009) 6986–6990
6987
O
O
OH
OMe
Ac2O
MeMg
I
OMe
-AcOH
OH
Benzofuranol (1)
O
O
O
4
O
5
3
CHO
O
Saponification
NaOH-MeOH
O
O
7
O
OMe
O
8
6
O
O
2
OMe
OMe
Et3N-induced
retro-Michael
OMe
O
O
O
9
O
11
O
10
Figure 1.
OR
X
RO-
X
O
I
O
O
A
12
(X = Br)
or
(X = Cl, OMs, OTf, NR3Br)
X
X
O
II
OR
O
B
O
Figure 2.
Table 1
group in 12. We envisioned that if the leaving ability of X group in
12 was slowed down, there might be a chance to form product II
that contains a similar structural scaffold as in the natural product
1. To identify an appropriate X group, we prepared a small series of
benzofurans 12 with various X group, including –Br, –Cl, –OAc,
–OMs, –OTf and –NEt3Br, and explored their reactions with sodium
alkoxides. To our surprise, we found that compound II can be
obtained dominantly over I by using N-benzofuran-3-ylmethyl
N,N,N-triethylammonium bromide salt (13a) as the substrate,
whereas other substrates only gave the directly substituted product
I. Although the exact mechanism is not clear, we believe that the
slowest leaving ability of –NEt3Br among the substituents (–Br, –Cl,
–OAc, –OMs, –OTf and –NEt3Br) we explored plays a critical role.
Herein we wish to present our investigation on this transformation,
improved synthesis of the natural product 1 and the construction of
a library of its analogs in details.
Reaction of ammonium bromides 13 with various sodium alkoxidesa
NR3Br
R'ONa
N(Et)2
R'OH, reflux
O
14
OR'
O
15
O
13
(a, R = Et; b, R = Me)
Entry
Substrate
R0
Temp
Time (min)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
13a
13a
13a
13a
13a
13a
13b
13b
13b
13b
13b
Mec
70
80
100
120
85
85
85
100
120
120
100
120
120
120
120
30
120
60
30
14a
14b
14c
14d
14e
14f
14f
14g
14h
14i
64
70
Etc
n-Pr
n-Bu
46 (tracee)
74 (10e)
64 (28e)
8 (83e)
68
i-Pr
t-Bud
t-Bud
i-Bu
88
85
90
88
9
10
11
i-Pentyl
n-Hexyl
C2H5(Me)CH
30
30
30
14j
2. Results and discussion
a
Unless specified, sodium alkoxides were prepared in situ.
Isolated yield.
Commercially available 20 equiv was used.
t-BuOK (20 equiv) was used.
b
c
The ammonium bromide salts 13a and 13b were prepared by
reacting benzofuran-3-ylmethyl bromide 126 with an excess of
Et3N or Me3N (in EtOH) in quantitative yields.8,9 The salts were
highly moisture-sensitive and had to be stored in a vacuum. To
achieve complete transformation, a large amount of sodium or
potassium alkoxides prepared in situ10 or obtained from a com-
mercially available source was used. As summarized in Table 1,
most commonly-used sodium alkoxides participated in this re-
action very well, and the expected 2-alkyloxy-3-methylene-2,3-
dihydrobenzofurans 14a-f were obtained in moderate to good
yields. In all cases, the directly substituted products (I) were not
observed. It was of note that using steric alkoxides or alkoxides
with a slightly longer chain, N,N-diethylaminomethyl benzofuran
159 was obtained as a by-product, especially in the case of t-BuOK
(entry 6), where 15 was obtained as the major product in 83%
d
e
Yield for compound 15.
yield. The production of compound 15 can be rationalized by a b-
H Hoffmann elimination11 from substrate 13a. To block this path,
N-benzofuran-3-ylmethyl N,N,N-trimethyl ammonium bromide
13b lacking a b-H was employed. As expected, all alkoxides par-
ticipated efficiently, and the expected products 14f–j (Table 1,
entries 7–11) were isolated in high yields, no by-product 15 was
observed.
To further examine the efficacy of this reaction and to expand
our collection of the unique class of compounds, a series of sodium
alkoxides prepared from sodium metal and several high boiling

6988
Y. Wang, Ao. Zhang / Tetrahedron 65 (2009) 6986–6990
alcohols including diols (Table 2, entries 1–4, 8) and mono end-
capped diols (entries 5–7, 9, 10) was employed. As demonstrated
in Table 2, all these alkoxides reacted with ammonium salt 13a
much quicker than the alkoxides listed in Table 1. All these re-
actions were completed in less than 30 min providing the corre-
sponding benzofuranols 14k–t in high yields. The mono-end
capped diols (entries 5–9) reacted more efficiently than non-
protected diols, with complete reaction in 10 min (entries 1–4). No
directly substituted, or Hoffmann elimination products were
observed.
4. Experimental
4.1. General procedure8,9 for the preparation of ammonium
salts 13a, 13b and 16
Et3N (10 mL) or Me3N (in EtOH, 10 mL, 33%) was added to a so-
lution of 3-bromomethylbenzofuran6,12 (15 mmol) in THF–CHCl3
(20 mL, vol/vol: 3:1). The mixture was stirred at rt overnight. After
removal of the solvents, a yellow residue was obtained which was
then washed with petroleum ether to afford an off-white solid in
quantitative yield. For salt 13a. 1H NMR (CDCl3, 300 MHz)
d 8.22 (s,
Table 2
1H), 7.83 (d, J¼6.6 Hz, 1H), 7.44 (d, J¼8.7 Hz, 1H), 7.28 (m, 2H), 5.15
Reaction of ammonium bromide 13a with various sodium alkoxidesa
(s, 2H), 3.51 (q, J¼7.2 Hz, 6H), 1.48 (t, J¼7.2 Hz, 9H). For 13b. 1H NMR
(CDCl3, 300 MHz)
d
8.22 (s, 1H), 8.04 (d, J¼6.9 Hz, 1H), 7.46 (d,
N(Et)3Br
NaOR'
J¼8.9 Hz, 1H), 7.27 (m, 2H), 5.33 (s, 2H), 3.44 (s, 9H). For salt 16. 1H
R'OH, 120 °C
O
14
OR'
NMR (CDCl3, 300 MHz)
d
8.11 (s, 1H), 7.88 (d, J¼9.0 Hz, 1H), 7.29 (s,
O
13a
1H), 7.10 (d, J¼8.4 Hz, 1H), 5.32 (s, 2H), 3.45 (s, 9H), 2.43 (s, 3H).
Entry
R0–
Time (min)c
Product
Yieldb (%)
4.2. General procedure for the preparation of 2-alkoxy-2,3-
dihydro-3-methylenebenzofurans 14a–t
1
2
3
4
5
6
7
8
9
10
HO(CH2)2–
HO(CH2)3–
HO(CH2)4–
HO(CH2)5–
MeOCH2CH2–
EtOCH2CH2–
i-PrOCH2CH2–
HO(CH2)2O(CH2)2–
MeO(CH2)2O(CH2)2–
EtO(CH2)2O(CH2)2–
30
30
30
30
10
10
10
10
5
14k
14l
82
82
72
71
85
86
88
88
79
75
14m
14n
14o
14p
14q
14r
14s
14t
To a solution of sodium alcoholate (20 equiv, obtained com-
mercially or prepared in situ from sodium metal with alcohol) in
the corresponding alcohol (25 mL), was added quickly salt 13a or
13b (1 equiv). The mixture was heated at reflux or 120 ꢀC (for high
boiling alcohols) for the time indicated in Tables 1 and 2. The re-
action was cooled, quenched with water, and extracted with Et2O
(3ꢁ40 mL). The combined ether phase was washed with brine,
dried over anhyd Na2SO4, and evaporated. The crude product was
purified with column chromatograph (petroleum ether/
CH2Cl2¼20:1) to give 2,3-dihydro-2-alkoxy-3-methylenebenzofur-
ans 14a–t.
5
a
Sodium alkoxides (in alcohol, 20% v/v) were prepared in situ.
Isolated yield.
Reaction completion time determined by TLC.
b
c
Encouraged by the results obtained above, we decided to com-
plete the synthesis of the natural product 1. Similarly, salt 16 was
prepared from 6-methylbenzofuran-3-ylmethyl bromide12 and
Me3N in EtOH in quantitative yield (Scheme 1). Treating salt 16
with excess MeONa (20 equiv) in MeOH under reflux provided 2-
methoxy-6-methyl-3-methylene-2,3-dihydrobenzofuran (17) in
83% yield. Following a literature procedure,3a,4,5 precursor 17 was
hydrolyzed to yield the target compound 1 in 85% yield. Compared
to the methods reported, our protocol was more efficient and
afforded benzofuranol 1 in three steps with 70% overall yield from
a more commonly used intermediate, 6-methylbenzofuran-3-yl-
methyl bromide.
4.2.1. 2-Methoxy-2,3-dihydro-3-methylenebenzofuran (14a)4
Yellow oil; MS (EI) 162 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.40
(d, J¼7.5 Hz, 1H), 7.22 (d, J¼8 Hz, 1H), 6.89 (m, 2H), 5.98 (t, J¼2.1 Hz,
1H), 5.70 (d, J¼2.1 Hz, 1H), 5.33 (d, J¼1.5 Hz, 1H), 3.52 (s, 3H).
4.2.2. 2-Ethoxy-2,3-dihydro-3-methylenebenzofuran (14b)4
Yellow oil; MS (EI) 176 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.39 (d,
J¼7.5 Hz, 1H), 7.21 (t, J¼7.8 Hz, 1H), 6.88 (m, 2H), 6.03 (t, J¼2.0 Hz,
1H), 5.68 (d, J¼2.1 Hz, 1H), 5.33 (d, J¼1.8 Hz, 1H), 3.92 (dq, J¼9.6,
7.2 Hz, 1H), 3.71 (dq, J¼9.6, 7.2 Hz, 1H), 1.29 (t, J¼7.0 Hz, 3H).
N(Me)3Br
NaOMe
HCl (2N, 2 equiv.)
THF, 85%
MeOH, reflux
O
OH
O
O
O
16
(83%)
benzofuranol (1)
17
Scheme 1.
3. Conclusions
4.2.3. 2-n-Propoxy-2,3-dihydro-3-methylenebenzofuran (14c)
Colorless oil; MS (EI) 190 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.39
We have developed an efficient strategy to construct a library of
2-alkoxy-3-methylene-2,3-dihydrobenzofurans by using benzofu-
ran-3-ylmethyl N,N,N-trialkylammonium bromide salts as the
substrate. Thus, treating these salts with various sodium/potas-
sium alkoxides which were readily prepared in situ from sodium
metal and simple alcohols, diols or mono-end capped diols affor-
ded the corresponding 2-alkoxy-3-methylene-2,3-dihydrobenzo-
furans in high yield. This convenient approach was applied to
prepare the natural product 1, which was obtained in three steps
with 70% overall yield from a common intermediate, 6-methyl-
benzofuran-3-ylmethyl bromide.
(d, J¼7.5 Hz, 1H), 7.22 (t, J¼7.8 Hz, 1H), 6.88 (m, 2H), 6.04 (t,
J¼2.0 Hz, 1H), 5.66 (d, J¼2.1 Hz, 1H), 5.32 (d, J¼2.1 Hz, 1H), 3.81 (dt,
J¼9.3, 6.6 Hz, 1H), 3.59 (dt, J¼9.3, 6.9 Hz, 1H), 1.68 (m, 2H), 0.96 (t,
J¼7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 160.9, 143.5, 130.6, 124.2,
121.0, 120.9, 110.4, 106.7, 106.5, 69.5, 22.9, 10.5. HRMS (EI) calcd for
C12H14O2 (Mþ) 190.0994, found 190.0997.
4.2.4. 2-n-Butoxy-2,3-dihydro-3-methylenebenzofuran (14d)
Colorless oil; MS (EI) 204 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.40
(d, J¼8.7 Hz, 1H), 7.22 (t, J¼8.4 Hz, 1H), 6.85 (m, 2H), 6.03 (t,
J¼1.8 Hz, 1H), 5.68 (d, J¼2.1 Hz, 1H), 5.32 (d, J¼1.8 Hz, 1H), 3.86 (dt,

Y. Wang, Ao. Zhang / Tetrahedron 65 (2009) 6986–6990
6989
J¼9.3, 6.6 Hz, 1H), 3.64 (dt, J¼9.3, 6.6 Hz, 1H), 1.63 (m, 2H), 1.42 (m,
4.2.12. 2-(30-Hydroxypropoxy)-2,3-dihydro-3-methylene
benzofuran (14l)
Colorless oil; MS (EI) 206 (Mþ); 1H NMR (CDCl3, 300 MHz)
2H), 0.93 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 160.9, 143.5,
130.6, 124.2, 121.0, 120.9, 110.3, 106.6, 106.5, 67.5, 31.6, 19.1, 13.7;
d
7.38
HRMS (EI) calcd for C13H16O2 (Mþ) 204.1150, found 204.1148.
(d, J¼7.2 Hz, 1H), 7.21 (t, J¼7.8 Hz, 1H), 6.90 (m, 2H), 6.03 (t,
J¼1.8 Hz, 1H), 5.68 (d, J¼1.8 Hz, 1H), 5.36 (d, J¼1.5 Hz, 1H), 3.97 (dt,
J¼9.6, 6.0 Hz, 1H), 3.79 (m, 3H), 2.22 (s, 1H), 1.88 (m, 2H); 13C NMR
4.2.5. 2-Isopropoxy-2,3-dihydro-3-methylenebenzofuran (14e)
Colorless oil; MS (EI) 190 (Mþ); 1H NMR (CDCl3, 300 MHz)
d
7.39
(CDCl3, 75 MHz) d 160.6, 143.1,130.6, 124.0,121.0,120.9,110.2,106.8,
(d, J¼7.5 Hz, 1H), 7.21 (t, J¼7.8 Hz, 1H), 6.87 (m, 2H), 6.08 (t,
106.2, 65.3, 60.1, 32.0; HRMS (EI) calcd for C12H14O3 (Mþ) 206.0943,
found 206.0946.
J¼2.0 Hz, 1H), 5.65 (d, J¼2.1 Hz, 1H), 5.28 (d, J¼1.8 Hz, 1H), 4.14 (m,
1H), 1.31 (d, J¼6.3 Hz, 6H); 13C NMR (CDCl3, 75 MHz)
d 160.8, 144.1,
130.6, 124.2, 121.0, 120.8, 110.4, 106.4, 105.4, 71.6, 23.6, 22.2; HRMS
4.2.13. 2-(40-Hydroxybutoxy)-2,3-dihydro-3-methylene-
(EI) calcd for C12H14O2 (Mþ) 190.0994, found 190.0995.
benzofuran (14m)
Colorless oil; MS (EI) 220 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.38
4.2.6. 2-t-Butoxy-2,3-dihydro-3-methylenebenzofuran (14f)
(d, J¼8.4 Hz, 1H), 7.21 (t, J¼7.6 Hz, 1H), 6.88 (m, 2H), 6.02 (t,
J¼3.0 Hz, 1H), 5.68 (d, J¼2.1 Hz, 1H), 5.32 (d, J¼1.8 Hz, 1H), 3.88 (dt,
J¼9.6, 6.0 Hz, 1H), 3.66 (m, 3H), 1.89 (s, 1H), 1.69 (m, 4H); 13C NMR
Colorless oil; MS (EI) 204 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.37
(d, J¼7.5 Hz, 1H), 7.20 (t, J¼7.8 Hz, 1H), 6.85 (m, 2H), 6.20 (t,
J¼2.0 Hz, 1H), 5.65 (d, J¼2.1 Hz, 1H), 5.28 (d, J¼1.8 Hz, 1H), 1.40 (s,
(CDCl3, 75 MHz) d 160.7,143.1,130.6,124.0,120.9,110.2,106.8,106.2,
9H); 13C NMR (CDCl3, 75 MHz)
d
160.9, 145.2, 130.5, 124.0, 121.0,
67.5, 62.1, 29.3, 25.9; HRMS (EI) calcd for C13H16O3 (Mþ) 220.1099,
found 220.1098.
120.6, 110.4, 105.8, 101.9, 28.8; HRMS (EI) calcd for C13H16O2 (Mþ)
204.1150, found 204.1141.
4.2.14. 2-(50-Hydroxypentoxy)-2,3-dihydro-3-methylene-
4.2.7. 2-i-Butoxy-2,3-dihydro-3-methylenebenzofuran (14g)
benzofuran (14n)
Colorless oil; MS (EI) 204 (Mþ); 1H NMR (CDCl3, 300 MHz)
d
7.41
Colorless oil; MS (EI) 234 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.38
(d, J¼7.5 Hz, 1H), 7.23 (t, J¼7.6 Hz, 1H), 6.91 (m, 2H), 6.05 (t,
J¼1.8 Hz, 1H), 5.69 (d, J¼2.1 Hz, 1H), 5.34 (d, J¼1.5 Hz, 1H), 3.65 (m,
1H), 3.39 (m, 1H), 1.96 (m, 1H), 0.96 (d, J¼6.3 Hz, 6H); 13C NMR
(d, J¼7.5 Hz, 1H), 7.21 (t, J¼7.6 Hz, 1H), 6.88 (m, 2H), 6.02 (t,
J¼1.6 Hz, 1H), 5.68 (d, J¼2.1 Hz, 1H), 5.32 (d, J¼1.8 Hz, 1H), 3.85 (dt,
J¼9.6, 6.0 Hz, 1H), 3.64 (m, 3H), 1.68 (m, 2H), 1.59 (m, 2H), 1.46 (m,
(CDCl3, 75 MHz)
d
160.8, 143.4, 130.6, 124.2, 121.0, 120.8, 110.3, 106.6
2H); 13C NMR (CDCl3, 75 MHz)
d 160.8, 143.3, 130.6, 124.1, 121.0,
(two), 74.3, 28.4, 19.3, 19.2; HRMS (EI) calcd for C13H16O2 (Mþ)
204.1150, found 204.1155.
120.9, 110.3,106.8,106.3, 67.6, 62.6, 32.2, 29.2, 22.1; HRMS (EI) calcd
for C14H18O3 (Mþ) 234.1256, found 234.1249.
4.2.8. 2-i-Pentoxy-2,3-dihydro-3-methylenebenzofuran (14h)
4.2.15. 2-(20-Meoxyethoxy)-2,3-dihydro-3-methylene
Colorless oil; MS (EI) 218 (Mþ); 1H NMR (CDCl3, 300 MHz)
d
7.39
benzofuran (14o)
(d, J¼7.8 Hz, 1H), 7.22 (t, J¼7.8 Hz, 1H), 6.88 (m, 2H), 6.03 (s, 1H),
Yellow oil; MS (EI) 206 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.38
5.68 (s, 1H), 5.32 (s, 1H), 3.88 (m,1H), 3.66 (m, 1H), 1.75 (m, 1H),1.55
(d, J¼7.5 Hz, 1H), 7.21 (t, J¼7.8 Hz, 1H), 6.88 (m, 2H), 6.10 (t,
J¼1.8 Hz, 1H), 5.69 (d, J¼2.1 Hz, 1H), 5.38 (d, J¼1.8 Hz, 1H), 3.92 (dt,
J¼9.6, 6.0 Hz, 1H), 3.76 (dt, J¼9.6, 6.0 Hz, 1H), 3.60 (t, J¼4.8 Hz, 2H),
(m, 2H), 0.92 (d, J¼7.8 Hz, 6H); 13C NMR (CDCl3, 75 MHz)
d 160.9,
143.4, 130.6, 124.2, 121.0, 120.9, 110.3, 106.7, 106.4, 66.2, 38.3, 24.8,
22.5; HRMS (EI) calcd for C14H18O2 (Mþ) 218.1307, found 218.1307.
3.38 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 160.7, 142.8, 130.5, 124.1,
120.9 (two), 110.2, 107.1, 106.2, 71.4, 65.9, 58.9; HRMS (EI) calcd for
4.2.9. 2-n-Hexoxy-2,3-dihydro-3-methylenebenzofuran (14i)
C12H14O3 (Mþ) 206.0943, found 206.0936.
Colorless oil; MS (EI) 232 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.40
(d, J¼7.8 Hz, 1H), 7.22 (t, J¼7.8 Hz, 1H), 6.90 (m, 2H), 6.04 (t,
J¼2.1 Hz, 1H), 5.68 (d, J¼2.4 Hz, 1H), 5.33 (d, J¼1.8 Hz, 1H), 3.88 (m,
1H), 3.66 (m, 1H), 1.66 (m, 2H), 1.34 (m, 6H), 0.91 (t, J¼3.8 Hz, 3H);
4.2.16. 2-(20-Ethoxyethoxy)-2,3-dihydro-3-methylene-
benzofuran (14p)
Brown oil; MS (EI) 220 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.38
13C NMR (CDCl3, 75 MHz)
d
160.9, 143.4, 130.6, 124.2, 121.0, 120.8,
(d, J¼7.5 Hz, 1H), 7.20 (t, J¼7.8 Hz, 1H), 6.87 (m, 2H), 6.11 (t,
J¼1.8 Hz, 1H), 5.69 (d, J¼2.1 Hz, 1H), 5.37 (d, J¼1.5 Hz, 1H), 3.92 (dt,
J¼9.6, 6.0 Hz, 1H), 3.78 (dt, J¼9.6, 6.0 Hz, 1H), 3.64 (t, J¼5.1 Hz, 2H),
3.53 (q, J¼7.0 Hz, 2H), 1.21 (t, J¼6.9 Hz, 3H); 13C NMR (CDCl3,
110.3, 106.6, 106.4, 67.9, 31.5, 26.5, 25.6, 22.5, 13.9; HRMS (EI) calcd
for C15H20O2 (Mþ) 232.1463, found 232.1464.
4.2.10. 2-(20-Methylpropoxy)-2,3-dihydro-3-methylene-
75 MHz) d 160.7, 142.9, 130.5, 124.1, 120.9, 110.2, 107.1, 106.2, 69.4,
benzofuran (14j)
66.5, 66.2, 15.0; HRMS (EI) calcd for C13H16O3 (Mþ) 220.1099, found
220.1095.
Colorless oil; MS (EI) 204 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.40
(d, J¼7.2 Hz, 1H), 7.22 (t, J¼7.5 Hz, 1H), 6.88 (m, 2H), 6.07 (s, 1H),
5.66 (d, J¼1.8 Hz, 1H), 5.30 (d, J¼10.2 Hz, 1H), 3.90 (m, 1H), 1.67 (m,
1H), 1.53 (m, 1H), 1.32 (d, J¼6.6 Hz, 1.6H), 1.28 (d, J¼6.3 Hz, 1.4H),
1.01 (t, J¼7.5 Hz, 1.6H), 0.93 (t, J¼7.5 Hz, 1.4H); 13C NMR (CDCl3,
4.2.17. 2-(20-Isopropoxyethoxy)-2,3-dihydro-3-methylene
benzofuran (14q)
Yellow oil; MS (EI) 234 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.38
75 MHz)
d
160.9, 160.8, 144.2, 144.1, 130.5, 124.2, 124.1, 121.0, 120.7,
(d, J¼7.5 Hz, 1H), 7.20 (t, J¼7.8 Hz, 1H), 6.88 (m, 2H), 6.12 (t,
J¼2.0 Hz, 1H), 5.68 (d, J¼2.4 Hz, 1H), 5.37 (d, J¼1.8 Hz, 1H), 3.91 (m,
1H), 3.80 (m, 1H), 3.64 (m, 3H), 1.17 (d, J¼7.2 Hz, 6H); 13C NMR
110.4, 106.6, 106.4, 106.3, 105.1, 78.0, 76.3, 29.9, 29.4, 21.2, 19.5, 9.8;
HRMS (EI) calcd for C13H16O2 (Mþ) 204.1150, found 204.1156.
(CDCl3, 75 MHz) d 160.7, 143.0, 130.5, 124.1, 120.9, 110.2, 107.0, 106.4,
4.2.11. 2-(20-Hydroxyethoxy)-2,3-dihydro-3-methylene-
71.8, 67.0, 66.7, 22.0, 21.8; HRMS (EI) calcd for C14H18O3 (Mþ)
234.1256, found 234.1251.
benzofuran (14k)
Colorless oil; MS (EI) 192 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.40
(d, J¼7.2 Hz, 1H), 7.23 (t, J¼7.8 Hz, 1H), 6.90 (m, 2H), 6.07 (t,
4.2.18. 2-(2-(2-Hydroxyethoxy)ethoxy)-3-methylene-2,3-
J¼1.8 Hz, 1H), 5.70 (d, J¼2.1 Hz, 1H), 5.36 (d, J¼1.8 Hz, 1H), 3.92 (m,
dihydrobenzofuran (14r)
1H), 3.82 (m, 3H), 2.34 (s, 1H); 13C NMR (CDCl3, 75 MHz)
d
160.4,
Yellow oil; MS (EI) 236 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.37
142.8, 130.6, 123.9, 121.1, 120.9, 110.3, 107.1, 106.3, 69.1, 61.5; HRMS
(EI) calcd for C11H12O3 (Mþ) 192.0786, found 192.0783.
(d, J¼7.8 Hz, 1H), 7.19 (t, J¼7.8 Hz, 1H), 6.87 (m, 2H), 6.07 (s, 1H),
5.68 (s, 1H), 5.34 (s, 1H), 3.92 (m, 1H), 3.78 (m, 1H), 3.69 (m, 4H),

6990
Y. Wang, Ao. Zhang / Tetrahedron 65 (2009) 6986–6990
3.57 (m, 2H), 2.77 (s, 1H); 13C NMR (CDCl3, 75 MHz)
130.6, 124.0, 121.0, 120.9, 110.3, 107.1, 106.2, 72.3, 70.0, 66.4, 61.5;
HRMS (EI) calcd for C13H16O4 (Mþ) 236.1049, found 236.1052.
d
160.6, 142.8,
1Hþ1H), 6.39 (s, 1H), 6.17 (s, 1Hþ1H), 5.57 (s, 1H), 5.31 (s, 1H), 3.54
(s, 1H), 2.32 (s, 3Hþ3H).
Acknowledgements
4.2.19. 2-(2-(2-Methoxyethoxy)ethoxy)-3-methylene-2,3-
dihydrobenzofuran (14s)
The authors thank the Chinese National Science Foundation
(grant 30772625), Shanghai Commission of Science and Technology
(07pj14104), as well as SIMM (SIMM0809KF-02) for financial
support.
Colorless oil; MS (EI) 250 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.37
(d, J¼7.2 Hz, 1H), 7.20 (t, J¼7.6 Hz, 1H), 6.87 (m, 2H), 6.09 (s, 1H),
5.67 (d, J¼2.1 Hz, 1H), 5.36 (d, J¼1.5 Hz, 1H), 3.94 (m, 1H), 3.80 (m,
1H), 3.70 (t, J¼4.2 Hz, 2H), 3.65 (t, J¼4.8 Hz, 2H), 3.54 (t, J¼3.9 Hz,
2H), 3.36 (s, 3H); 13C NMR (CDCl3, 75 MHz)
d 160.7, 142.9, 130.6,
Supplementary data
124.1, 120.9 (two), 110.3, 107.1, 106.3, 71.8, 70.4, 70.2, 66.3, 58.9;
HRMS (EI) calcd for C14H18O4 (Mþ) 250.1205, found 250.1206.
Copies of 1H and 13C NMR spectra of all the new compounds and
the natural product 1. This material is available free of charge via
the Internet. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2009.06.049.
4.2.20. 2-(2-(2-Ethoxyethoxy)ethoxy)-3-methylene-2,3-
dihydrobenzofuran (14t)
Colorless oil; MS (EI) 264 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.37
(d, J¼7.8 Hz, 1H), 7.20 (t, J¼7.8 Hz, 1H), 6.87 (m, 2H), 6.09 (t,
J¼1.8 Hz, 1H), 5.67 (d, J¼2.1 Hz, 1H), 5.36 (d, J¼1.5 Hz, 1H), 3.92 (dt,
J¼9.6, 6.0 Hz, 1H), 3.82 (dt, J¼9.6, 6.0 Hz, 1H), 3.71 (t, J¼4.8 Hz, 2H),
3.65 (t, J¼4.5 Hz, 2H), 3.57 (t, J¼4.5 Hz, 2H), 3.51 (q, J¼7.2 Hz, 2H),
References and notes
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1.19 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d 160.7, 143.0, 130.5,
124.1, 120.9 (two), 110.3, 107.1, 106.3, 70.6, 70.2, 69.7, 66.5, 66.3,
15.0; HRMS (EI) calcd for C15H20O4 (Mþ) 264.1362, found 264.1362.
4.3. N-((Benzofuran-3-yl)methyl)-N-ethylethanamine (15)9
Yellow oil; MS (EI) 203 (Mþ); 1H NMR (CDCl3, 300 MHz)
d 7.72
(d, J¼7.5 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J¼7.8 Hz, 1H), 7.26 (m, 2H),
3.71 (s, 2H), 2.56 (q, J¼7.1 Hz, 4H), 1.08 (t, J¼7.2 Hz, 6H); 13C NMR
(CDCl3, 75 MHz) d 155.4, 142.7, 128.2, 124.0,122.2, 120.5, 118.2,111.2,
46.8, 46.6, 11.9; HRMS (EI) calcd for C13H17NO (Mþ) 203.1310, found
203.1318.
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4.4. 2-Methoxy-6-methyl-3-methylene-2,3-dihydrobenzo
furan 173a,4,5
To a solution of CH3ONa (50%, 760 mg, 7 mmol) in MeOH
(10 mL), was added quaternary ammonium salt 16 (100 mg,
0.35 mmol). The mixture was heated at 70 ꢀC for 2 h. The solvent
was evaporated, and the residue was taken up in cold water. The
mixture was extracted with ether, washed with brine, and evapo-
rated. The residue was purified by silica gel column chromatograph
(petroleum ether/CH2Cl2¼5:1) to afford the title compound 17 as
a colorless oil (51 mg, 83%).
MS (EI) 176 (Mþ); 1H NMR (CDCl3, 300 MHz)
d
7.28 (d, J¼7.5 Hz,
1H), 6.74 (d, J¼7.8 Hz, 1H), 6.71 (s, 1H), 5.97 (t, J¼1.8 Hz, 1H), 5.62 (d,
J¼1.8 Hz, 1H), 5.27 (d, J¼0.9 Hz, 1H), 3.51 (s, 3H), 2.34 (s, 3H); 13C
NMR (CDCl3, 75 MHz)
d 161.1, 142.9, 141.3, 121.9, 121.5, 120.6, 110.8,
107.2, 105.6, 54.2, 21.8; HRMS (EI) calcd for C11H12O2 (Mþ) 176.0837,
found 176.0837.
4.5. 6-Methyl-3-methylene-2,3-dihydrobenzofuran-
2-ol (1)3a,4,5
This compound was prepared from 17 by using a literature
procedure3a,4,5 in 85% yield. As stated in the literature, this com-
pound is not stable, and co-existed with a small amount (~20%) of
its hemiacetal-opened aldehyde based on the 1H NMR spectra. MS
11. Chandran, K.; Nithya, A.; Sankaran, K.; Gopalan, A.; Ganesan, V. Bull. Mater. Sci.
2006, 29, 173–179.
12. (a) Naef, R.; Jaquier, A.; Velluz, A.; Bachofen, B. Chem. Biodivers. 2004, 1, 1870–
1879; (b) De Boggiatto, M. V.; De Heluani, C. S.; De Fenik, I. J. S.; Catalan, C. A. N.
J. Org. Chem. 1987, 52, 1505–1511; (c) Suzuki, T.; Tanemura, K.; Horaguchi, T.;
Shimizu, T.; Sakakibara, T. J. Heterocycl. Chem. 1992, 29, 423–429.
(EI) 162 (Mþ); 1H NMR (CDCl3, 300 MHz)
d
9.68 (s, 1H), 7.26 (d,
J¼4.5 Hz, 1Hþ1H), 7.07 (s, 1H), 6.74 (d, J¼7.5 Hz, 1Hþ1H), 6.67 (s,